Drug Resistance in Trypanosoma brucei

Experimenting with trypanosomes, Paul Ehrlich (1854–1915) observed that he could select for resistance by sublethal exposure to drugs, and he went on to define complementary groups based on patterns of cross-resistance. Ehrlich proposed to use these laboratory-selected drug-resistant lines to phenotypically classify newly identified trypanocides [1]. Since these pioneering studies, African trypanosomes have remained model organisms to study the mechanisms of drug action and drug resistance. After over 100 years of research on the mechanisms of drug resistance in African trypanosomes, reduction of drug import has crystallized as the predominant cause of resistance. This was recognized by classical studies in the 1930s and substantiated by recent approaches implementing next-generation sequencing and reverse genetics. More recently, the amenability of Trypanosoma brucei brucei to reverse genetic engineering has proven how nutrient transporters play key roles in the uptake of—and susceptibility to—clinically used trypanocides. These include aquaglyceroporin 2 and the adenosine transporter 1 for melarsoprol and pentamidine, and the amino acid permease 6 for eflornithine. Loss-of-function mutations in such transporters are viable because of the high degree of redundancy in the nutrient import machinery of T. brucei bloodstream forms. Thus T. brucei are, on the one hand, fascinating organisms that continue to provide new insights into the biology of eukaryotes; on the other hand, they are lethal pathogens of tropical Africa.